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A vial of Gilead's remdesivir, which is being closely watched as a potential COVID-19 treatment.

With society clamoring for something—anything—that can stem the rapidly rising death toll of the COVID-19 pandemic, Gilead Sciences’ antiviral remdesivir has emerged as a closely-watched treatment option. Laboratory studies of other coronaviruses suggested it might be able to take down this one, and as the outbreak took hold in China in January, it was among the first treatments that doctors tried.

Now, with cases worldwide at nearly 2.5 million, scrutiny of data coming out of clinical trials of the drug has reached fever pitch. When the health-focused news site Stat posted a story based on leaked video of a University of Chicago clinician talking optimistically about remdesivir’s possible effectiveness, it didn’t just prop up Gilead’s stock price; it lifted the entire stock market.

With each new anecdote, whether about an individual patient or a hunch from a doctor running a trial, the pressure on Gilead mounts. If any of the five late-stage clinical studies underway show that remdesivir works, Gilead will need to make a lot of it, and fast.

Gilead declined interview requests, but C&EN talked with manufacturing experts with experience in scaling up drugs amid crises to understand the challenge Gilead faces and how fast the firm—or any company developing a drug that might be effective against COVID-19—could reasonably meet demand. Past situations provide some guidance, though all concede that none of them matches the level of urgency being felt now.

Drug manufacturing today is like a bucket brigade, explains Princeton University chemist Paul Reider, who previously held chemistry leadership positions at Amgen and Merck & Co. One supplier sends raw materials to another, which uses those basic chemicals to do the first step in the synthesis of a molecule—say, creating a simple side chain. The result gets passed on to another company in the brigade, which performs the next step, and so on. Two or more of those bucket lines might converge to put together the now-complex pieces into the final molecule.

The efficiency of the brigade varies from drug to drug. One variable is the complexity of the molecule. The antimalarial hydrochloroquine, also being tested in COVID-19, is at the easy end of the spectrum. Making it in large quantities, if the need arises, will require little more than high-quality manufacturing capacity. Remdesivir, with its six chiral centers, is “a medium complexity project,” says Ian Davies, director of internal and external scientific relationships for the Princeton Catalysis Initiative.

But beyond the molecule itself, ease of scale-up has much to do with a company’s manufacturing design philosophy, Davies notes. While all firms design a safe route, “most companies approach this on sufficiency,” rather than efficiency, says Davies, who previously led Merck & Co.’s process chemistry group. They estimate a drug’s market size and likely price tag, and weigh that against how much manufacturing the active ingredient will cost. If the margins look good enough, many companies won’t invest much in making a process more efficient, he says.

And when it comes to remdesivir, experts say Gilead might not have been inclined, or even had the time, to make the process as efficient as it could be. Gilead developed the compound during the 2014 Ebola virus outbreak in West Africa and sped it along with the goal of testing it before the outbreak waned. The process likely reflects the anticipated demand for an Ebola treatment: the 2014 Ebola outbreak saw 29,000 cases over 2.5 years; the current coronavirus pandemic is approaching 2.5 million cases in under 5 months.

As the scope of the pandemic widens, Gilead has been open about the challenges of manufacturing the drug. The firm says it typically takes 9 to 12 months to make an antiviral like remdesivir, but that since January it has shrunk the timeline to 6 to 8 months. “We continue to work on optimizing the chemical synthesis processes,” the company states.

In a public communication in early April, CEO Daniel O’Day outlined a series of measures Gilead was taking to increase access to remdesivir. At the time, the company said it had on hand enough active ingredient to create about 1.5 million doses, enough for roughly 140,000 treatment courses, based on a 10-day regimen. The company has been working to increase both internal capacity and external partnerships to generate an additional 500,000 courses by October, 1 million courses by the end of the year, and, if needed, several million courses in 2021.

The ramp up is significant. But global demand, which could include both treatment for the ongoing pandemic and government stockpiling, could dwarf those figures if the drug proves to be beneficial in treating COVID-19.

Manufacturing experts point to the astronomical demand for government stockpiles of the influenza treatment Tamiflu amid the H1N1 outbreak, which began in 2004. The situations have important differences—Tamiflu is oral, while remdesivir is intravenous, meaning its utility, if proven, would be more limited—but the thought exercise for how to tackle the problem is probably similar.

Indeed, David LaPre, who led the team at Roche that scaled up Tamiflu production, says the first question for companies with promising COVID-19 treatments is how many doses they will need. “There were a lot of debates as to what’s the right number, and I’m sure that’s the problem people are facing today as they think about antivirals as a weapon in our arsenal against COVID-19,” says LePre, who is now a pharmaceutical consultant. “I sense that now, like then, there’s not going to be a precise number—you basically have to pick one that makes sense between your own thinking and the thinking of health authorities. That becomes the target.”

In 2005, Roche based its Tamiflu target on several case studies that pegged demand at more than 1 billion doses, LaPre says.

Another layer of complexity is the vast network of partners—the bucket brigade—involved in taking a drug from raw materials to a finished product delivered to a hospital or pharmacy. Decades ago, big pharma firms performed many of those steps in-house across a handful of manufacturing sites. During the late 1990s, when Merck was preparing for a surge in demand for the HIV treatment Crixivan, “we picked up every available piece of equipment we needed” from sites in several states, Reider, who worked on Crixivan, recalls.

Roche, which licensed Tamiflu from Gilead in 1996, also was able to expand its internal capacity while at the same time building an external supply chain. Between 2005 and 2007, Roche ended up providing roughly 200 million courses of Tamiflu for government stockpiles around the globe.

But over the past 15 years, drug companies have scaled back their internal capacity. “People don’t recognize how many pieces are touched” by a vast network of contract manufacturing partners around the globe, says James Bruno, president of the consulting firm Chemical and Pharmaceutical Solutions. And “if one of those pieces fails,” it creates a bottleneck that is felt down the entire bucket brigade.

Gilead typically outsources the synthesis of its drugs through late-stage intermediates, performing the last critical steps in-house. And while it says it is trying to increase its own capacity, its first step was likely “to quickly scan the globe as to who has the right capability that can be brought to bear,” LaPre says.

“What I would do, which is what we did, is take a small team and lock them in a conference room and say, ‘We’re not leaving until this is done,’” LaPre says. But that can’t be done today, he acknowledges, and “it gets difficult to do after you’ve been on Zoom for a few hours.”

Technology transfer, or the process of teaching a partner how to do a difficult chemical step at scale, is particularly hard under current conditions. “You don’t just dump the technology over the fence,” Princeton’s Reider says. Typically, an internal expert “will go live someplace out of a suitcase for weeks at a time” while making sure a contract manufacturer is performing a synthetic step properly.

“Gilead is really good at doing this,” says Reider, who has consulted for Gilead on projects that predate remdesivir. In fact, some of Gilead’s current process development and manufacturing team helped out while Roche scaled up Tamiflu, he notes.

Others agree that the company is well prepared to tackle the crisis. “They’ve lived through a couple of these spikes before with their antivirals,” Bruno notes.

Other drugmakers face similar manufacturing challenges. Beyond the dozens of firms with drugs that were developed for other diseases and now are being tested against COVID-19, many are working at a furious pace to start trials of antivirals tailored to coronaviruses.

Pfizer, for one, recently announced it is working on a new antiviral that it hopes to put into clinical studies by the third quarter. Even though the compound has yet to be tested in humans, the company is doing extensive work on the manufacturing route—work typically done much later in the drug development process.

“We’re working with external CROs [contract research organizations] in terms of producing the raw and clinical materials, and also have colleagues in-house working on optimizing the chemistry and synthetic route,” says Charlotte Allerton, head of medicine design at Pfizer. The goal is to have an efficient route for producing large-scale quantities of the active ingredient ready to go if it proves to be effective.

“Right now,” LaPre says, “if you have something that’s promising, if you haven’t already done so, you should at least be conducting a tabletop exercise to figure out: What are we going to do to meet the high end of the potential demand? It doesn’t cost anything to cook up a plan.”

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Comments

R.K.Sarma (April 21, 2020 2:56 AM)

Excellent and realistic analysis of the situation. China used to be a good source for basic starting materials. Now that option is as good as closed. Two Indian companies are are interested in its manufacture, I understand.

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Didi (April 22, 2020 10:34 PM)

China's pharmaceutical API and FDF production was throughout the developments since January continued (like Food Industry) wherever possible in China to meet both the domestic and export demand. Even during the lunar new year (spring festival) week, when Wuhan was in lock down, pharmaceutical companies arranged for manufacturing and Q-function people not only in API but also in FDF and suitable companies initiated R&D for synthesis and GMP scale-up. To authorized contract manufacturers additional, capable capacities, e.g. for intermediates, are established. The Chinese authorities do not put restrictions on producers to fulfill their export obligations and strongly support the manufacture of all pharmaceutical materials for both domestic and global demand to warant uninterrupted supply chains. This observation has even been mentioned by the US FDA.

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K (April 22, 2020 5:01 PM)

"Gilead declined interview requests". Yet the article goes on to speculate about something that might not even be a problem with manufacturing one of their products, let alone whether or not remsvidir will even be effective with COVID-19. There are already too many news articles and journal/preprint papers being published on this that are poor journalism and/or poor science.